Overlooking evolution: a systematic analysis of cancer relapse and therapeutic resistance research

Abstract

Cancer therapy selects for cancer cells resistant to treatment, a process that is fundamentally evolutionary. To what extent, however, is the evolutionary perspective employed in research on therapeutic resistance and relapse? We analyzed 6,228 papers on therapeutic resistance and/or relapse in cancers and found that the use of evolution terms in abstracts has remained at about 1% since the 1980s. However, detailed coding of 22 recent papers revealed a higher proportion of papers using evolutionary methods or evolutionary theory, although this number is still less than 10%. Despite the fact that relapse and therapeutic resistance is essentially an evolutionary process, it appears that this framework has not permeated research. This represents an unrealized opportunity for advances in research on therapeutic resistance.

Figure 1. The Evolution of Resistance.

An evolutionary view of cancer reveals that therapy selects for resistant cells among an initially heterogeneous population. When the patient relapses, the tumor is composed of a new diverse population of resistant cells generated by further genetic alterations.

Figure 2. Use of evolution terms in relapse literature.

Proportion of abstracts on therapeutic resistance/relapse using each evolution term in 6,228 PubMed abstracts going back to 1915.

Figure 3. Evolution terms in abstracts.

Proportion of abstracts each year on therapeutic resistance/relapse using at least one evolution term out of 6,228 PubMed abstracts going back to 1915 (there was no use of evolution terms before 1983).

Figure 4. Explanations for resistance.

Number of papers using each explanation for resistance out of 22 coded papers.

Figure 5. Measurement of heterogeneity in recent articles.

Numbers of papers measuring each type of heterogeneity out of 22 coded articles. Only 2 of 22 papers measured epigenetic or genetic within-tumor heterogeneity.